This project will define the effects of concentrated air particles in an animal model of chromic bronchitis. It will determine the role of concentration vs composition in producing adverse effects. The project focuses upon discovery of mechanisms of death and morbidity caused by ambient air particles in animals with pre-existing pulmonary inflammation and airway hyperresponsiveness. Specific aims are: 1) To define the extent of mortality resulting from exposure to various levels of concentrated ambient air particles (CAPs) using normal adult rats and rats with chronic bronchitis; and 2) To determine the mechanisms by which inflammation contributes to mortality and morbidity from exposure to CAPs in the rat model of chronic bronchitis, and 3) To characterize the degree of airway obstruction and hypoventilation present in rats with chronic bronchitis that could lead to increased morbidity and mortality with exposure to CAPs. To assess effects of ambient air particles, animals will be exposed using the Harvard Ambient Particulate Concentration (HAPC), a newly developed device that can increase ambient particle concentrations up to thirty times ambient levels without changing the physical or chemical characteristics of the particles. The exposed animal populations will model human populations and adverse effects including increased mortality that have been identified epidemiologically. Concentrating airborne particles for use in exposures will permit the populations studied in the laboratory to be of a size to see the modeled effect and a size unable to test mechanistic hypotheses. Exposures will take place in Boston, MA, which has a typical fine particle urban aerosol ranging from 5-15 gu/m3 with transported sulfur-containing acidic particles during the summer and local combustion product particulate in winter. With Core support, extensive physical, chemical, andmicrobiologic analysis of the exposure aerosol will be carried out with correlation between these parameters and biologic responses of the animals. Established physiologic methods will probe airway responses and their mechanisms. Cell and molecular biology methods will test mechanistic hypotheses on the role of pro-inflammatory mediators in the development of morbidity and mortality. The novel application of of sophisticated techniques in our proposed studies will offer new insights into mechanisms of toxicity of ambient air particles.